Abstract Millions of individuals in the United States undergo surgery every year for medically necessary conditions and are at risk for developing chronic pain especially following traumatic procedures like orthopedic surgery. Excessive inflammation and unresolved pain remain leading causes of morbidity, in particular among the rapidly growing elderly population. Our long-term goal is to define the mechanisms that underlie the conversion of acute to persistent postoperative pain, and to provide safe and effective approaches to reduce this potentially devastating complication. In the proposed study, we will model postoperative pain using a clinically relevant model of orthopedic surgery (tibial fracture) combined with stress, which is a common to virtually every patient undergoing major surgery. The overall objective of the work proposed in this project is to evaluate the role of complementary and integrative health approaches to reduce, and possibly resolve, postoperative pain. Our central hypothesis is that surgery-induced neuroinflammation is crucial to the modulation of postoperative pain, and is exacerbated by a stressful event. Targeting of pro-resolving and vagal-mediated signaling can reverse this persistent pain. This hypothesis is based on preliminary data acquired in the applicants? laboratories, and will be tested by pursuing 3 specific aims: 1) Analyze the effects of stress and sex on surgery-induced neuroinflammation and pain behavior; 2) Determine the effects of natural compounds including docosahexaenoic acids, menthol, and eucalyptol, on neuroinflammation and pain behavior after orthopedic surgery; and 3) Characterize the ability of bioelectronic approaches (electroacupuncture and vagus nerve stimulation) to reduce pain and neuroinflammation after orthopedic surgery. Feasibility for these models and techniques has been established in the applicants? hands. In this innovative approach, novel complementary bioelectronic strategies, including minimally invasive vagus nerve stimulation, circuit mapping methods, and postmortem analyses of clarified tissues will be combined with rigorous immunophenotyping and behavioral testing to define and modulate pain-related signaling after surgery. The rationale for the proposed research is that successful completion will advance and expand our understanding of how multiple complementary and integrative health approaches affect fundamental molecular mechanisms of relevance to pain signaling and perioperative recovery. Such knowledge is highly significant because it has the potential to improve surgical outcome, reduce opioid requirements, and enhance quality of life for millions of patients in the United States.